Epidemiological and animal studies have identified many potential mechanisms by which airborne particles may impact health. However, the relative importance of these potential pathways remains not well understood. Our competing renewal is a molecular epidemiologic study with the overall goal to investigate distinct biologic pathways that mediate the detrimental effects of exposure to particulate matter (PM), building upon our productive studies in this population during our last funding period. We have focused on particles from fossil fuel power plants and welding fume as a model to evaluate the health effects of metallic particles. We will test hypotheses regarding these exposures using three endpoints for hypothesis testing: 1) autonomic function, as measured by heart rate variability (HRV); 2) vascular function, as measured by blood pressure and arterial stiffness; and 3) epigenetic changes, measured by global methylation in DNA from peripheral blood and nasal mucosa brushings of exposed individuals. We will investigate potential PM mechanisms in a cohort of particle- exposed workers with well characterized exposure to PM2.5. We have shown that inhaled PM is associated with heart rate variability changes, and evidence of oxidative DNA damage, as well as systemic inflammation. Moreover, we have shown that metallic fume exposure produces systemic changes in gene expression in peripheral blood of exposed individuals. This cohort is advantageous because of the direct access to the environment in which to measure personal exposures directly and accurately and the high rate of participation and cooperation. To test our hypotheses, our first aim will assess how short-term (hours) exposure to particles (PM) affects cardiac autonomic function (as measured by changes in heart rate variability; HRV); and vascular function as measured by changes in blood pressure and arterial stiffness measured by Pulse Wave Analysis (PWA). Our second aim will assess whether long-term (years) PM exposure to metallic PM is associated with increased risk of impaired vascular function, and systemic inflammation. Our third aim will assess personal PM exposure in relation to epigenetic changes in peripheral blood and in nasal epithelial brushings, as measured by epigenome-wide DNA methylation. Our fourth aim is exploratory in which we will mine data mining from our existing gene expression results, and further assess the relationship between plasma profiles and the observed autonomic, vascular and inflammatory responses to PM. We will assess specific candidate biomarkers of early and chronic responses to metal-rich particulate exposures based on global gene expression profiles among this cohort. Our multidisciplinary team, combined with an established population, allows a unique opportunity to combine innovative methods with established epidemiologic methods for investigating particulate-associated cardiovascular and systemic effects in humans.